The present invention relates to nitroimidazooxazine and nitroimidazooxazole analogues, to their preparation, and to their use as drugs effective against Mycobacterium tuberculosis and as anti-protozoal agents, either alone or in combination with other treatments.
Tuberculosis remains a leading infectious cause of death worldwide (having a mortality estimated to be 1.3 million in 2008), with a recent resurgence attributable to an enhanced susceptibility in HIV patients, as well as the increasing incidence of multidrug-resistant strains and the emergence of extensively drug resistant strains. Current drug therapy for tuberculosis is long and complex, involving multidrug combinations (usually isoniazid, rifampin, pyrazinamide and ethambutol) given daily for in excess of 6 months. Furthermore, these drugs are relatively ineffective against the persistent form of the disease, which is suggested to occur in a significant proportion of cases (Ferrara et al., 2006). Second-line drugs used in lengthy combination therapies for multidrug resistant diseases (typically over 2 years) mostly have reduced potency or greater toxicity than existing first-line agents. Frequently, incomplete treatment is administered, leading to high relapse rates and increased drug resistance, underscoring the urgent need for new, more effective drugs.
Chagas disease affects about 9 million people, principally in South America, and results in about 14,000 deaths annually. It is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans by blood-sucking bugs. The two drugs currently available for treatment, nifurtimox and benznidazole, show efficacy that is limited to the acute phase of the disease and to only some pathogen strains. These drugs also give serious side effects, and this, together with the lengthy and expensive treatment required, leads to inadequate patient compliance and the development of drug resistance (Cavalli et al., 2009).
Leishmaniases affect almost 12 million people in nearly 90 countries and result in about 51,000 deaths annually. They are particularly prevalent on the Indian subcontinent and in east Africa, where the parasite Leishmania donovani is the causative agent. This parasite is transmitted to humans through the bite of female sandflies and is responsible for the most severe form, visceral leishmaniasis (kala-azar), which causes chronic disease in the liver and spleen and is fatal unless treated by chemotherapy. First-line treatments are the antimonials meglumine antimonate (Glucantime) and sodium stibogluconate (Pentostam), discovered more than 50 years ago, which present severe, undesirable side effects. Their administration in low doses over a longer time has resulted in growing drug resistance such that they can no longer be used in India (Cavalli et al., 2009). Second-line agents suffer from similar toxicity concerns, illustrating the real need for safer, more effective treatments.
It is therefore highly desirable to provide new nitroimidazooxazine and nitroimidazooxazole analogues with unexpectedly high potency against both aerobic (replicating) and hypoxic (latent or persistent) cultures of Mycobacterium tuberculosis, for use as anti-tubercular drugs, and/or with unexpectedly high potency against Trypanosoma cruzi or Leishmania donovani for use as anti-protozoal agents, and for the treatment of other microbial infections.